CONTRACEPTIVES CONTRACEPTIVES AND SEX HORMONESAND SEX HORMONES

STEROID SEX HORMONES ARE STEROID SEX HORMONES ARE NECESSARY :NECESSARY :

CONCEPTION

EMBRYONIC MATURATION

DEVELOPMENT OF PRIMARY AND SECONDARY SEXUAL CHARACTERISTIC

HORMONE SYNTHESIS AND RELEASEHORMONE SYNTHESIS AND RELEASECONTROLLED BY LH, FSH

REGULATED BY GnRHOVARY, TESTIS, ADRENAL GLAND,

PLACENTACHOLESTEROLPrimarily used : - Replacement therapy - Contraceptive preparations

Classification :Classification :

I. Estrogens*Steroidal, natural : Estradiol,Estrone, Estriol *Steroidal, synthetic : Ethinyl estradiol, Mestranol, Quinestrol* Nonsteroidal, synthetic : Diethylstilbestrol, Chlorotrianisene, MethallenestrilII. Antiestrogens* Clomiphene* Tamoxifen

III. ProgestinsIII. Progestins* Natural : Progesterone* Natural : Progesterone* Synthetic : Hydroxyprogesterone, * Synthetic : Hydroxyprogesterone, Medroxyprogesterone asetat, Medroxyprogesterone asetat,

Megestrol, Megestrol, Gestodene, Norgestimate, Gestodene, Norgestimate, Desogestrel Desogestrel

IV. Antiprogestin :IV. Antiprogestin : Mifepristone Mifepristone

V. Androgens : V. Androgens : Natural : Testosterone Natural : Testosterone Synthetic : Testosterone cypionate Synthetic : Testosterone cypionate Fluoxymesterone Fluoxymesterone Testolactone Testolactone

Danazol Danazol

VI. Antiandrogens :VI. Antiandrogens : Cyproterone acetate Cyproterone acetate Flutamid Flutamid

ESTROGENSESTROGENSPHARMACODYNAMIC EFFECTSPHARMACODYNAMIC EFFECTS

*Growth and development - development and maturation of female internal and external genitalia - growth of myometrium growth and development of the endometrial lining *Menstrual cycle - ovarian follicular development *Systemic metabolism *Influence libido and mood

PHARMACOKINETICSPHARMACOKINETICS*Natural estrogens : - Abs. from GIT, skin, mucous membrane > rapidly ( IM > rapidly) - Orally : rapidly metabolized *Synthetic estrogens : - Oral adm. : abs. >rapidly , metabolized > slowly - Prolonged action and potency*Binds to SHBG (strongly) and albumin*Enterohepatic circulation

ADVERSE EFFECTSADVERSE EFFECTS Nausea -Vomiting Endometrial hyperplasia -Edema Hyperpigmentation -Hypertension Migren headaches -Cholestasis

Contraindicated :– Estrogen-dependent/responsive carcinoma– Liver disease– Thromboembolic disease

Note : – DES adenocarcinoma of the vagina

THERAPEUTIC USESTHERAPEUTIC USES

Postmenopausal hormone therapy- hot flashes, sweating, atrophic vaginitis, osteoporosis- ♀≠ hysterectomy = estrogen + progestin

Primary hypogonadism- Estrogen + progestin

Contraception Androgen-dependent prostatic tumors

CLOMIPHENE AND TAMOXIFENCLOMIPHENE AND TAMOXIFEN

Nonsteroidal antiestrogenic Competitive antagonist/weak agonists Therapeutic uses : - Clomiphene : infertility - Tamoxifen : estrogen-dependent tumors of the breast Side effects : - hot flashes, nausea, vomiting, ovarian enlargement.

PROGESTINSPROGESTINS

Important natural progestin : progesteroneSynthesized by ovaries, testes, adrenalsPharmacodynamic effects : - Embryo implantation

- Inhibits uterine contraction- Triglycerides & HDL , LDL

PHARMACOKINETICSPHARMACOKINETICS

Progesterone (natural progestins)– Rapidly abs.– Adm. : IM (Orally : ineffective)– E. ( urine ) : pregnanediol glucoronide

Synthetics– Metabolized : slowly

ADVERSE EFFECTSADVERSE EFFECTS

Weight gain Thrombophlebitis Edema Depression Pulmonary embolism

THERAPEUTICS USESTHERAPEUTICS USES

- Oral contraception - Endometrial cancer- Replacement Therapy- Dysmenorrhea- Endometriosis- Hirsutism- Uterine bleeding

ANTIPROGESTINANTIPROGESTINMIFEPRISTONE ( RU 486 )

-Competitive receptor antagonist/partial agonist

-Ind.: medical abortion, post coital contraceptive

-SE.: heavy bleeding, nausea, vomiting, anorexia, abdominal pain, fatigue

HORMONAL HORMONAL CONTRACEPTIVESCONTRACEPTIVES

Mechanism : Preventing ovulation Impairing gametogenesis

Interfering with gestation

Types of hormonal Types of hormonal contraceptivescontraceptives

1.Combination Oral Contraceptives- estrogen + progestin monophasic, biphasic, triphasic prep. estrogens : ethinyl estradiol, mestranol progestins: norethindrone, norgestrel, levonorgestrel, norgestimate, desogestrel- 21 days packs + 7 days pill free mens induction- most frequently- highly efficacious

2. Sequential preparations2. Sequential preparations -Estrogen alone ( 14 days), followed by -Estrogen alone ( 14 days), followed by estrogen-progestin comb. ( 7 days) estrogen-progestin comb. ( 7 days)

3. Postcoital contraceptives3. Postcoital contraceptives -Morning after pills -Morning after pills -High-dose estrogen/ -High-dose estrogen/ estrogen-progestin estrogen-progestin -Twice daily for 5 days -Twice daily for 5 days

4. Progestin-Only Contraceptives Efficacious < a.Progestin pills (“mini pills”) - norethindrone or nosgestrel, every day b.Progestin implants -norgestrel ( up to 5 years ) c. Progestin IM -MPA 150 mg, every 3 months

-Norethindrone enantate 200 mg, every 2 month

5. Cycloprovera :5. Cycloprovera : MPA 25 mg + Estradiol cypionate 5 mg MPA 25 mg + Estradiol cypionate 5 mg Monthly injectable Monthly injectable

Drugs which interfere with oral contraceptives :

Rifampicin, Phenobarbital, Phenytoin, Isoniazid, Griseofulvin metabolism (efficiency )

Broad spectrum antibiotics absorption

Pharmacokinetic ParametersPharmacokinetic Parameters

PlasmaDrug Administration Absorption Half-life Protein Binding Disposition

Estradiol Oral (esters), IM, topical, Rapid if 30 min 50%-80% SHBG, M (main), *R Suppository micronized 18%-48% albuminEthinyl Estradiol Oral Rapid 6-20 hr 98% albumin M (main), *R Progesterone IM Poor 5 min 50% CBG; M, R 48% albuminLevonorgestrel Oral Rapid 11-45 hr 80% SHBG MNorethindrone Oral Rapid 5-14 hr 60%-70% SHBG M 30%-35% albuminClomiphene citrate Oral Rapid 4-10 hr (trans), - M >18 hr (cis) Tamoxifen citrate Oral Slow 7 days Albumin -Mifepristone Oral <25% 10-24 hr 95% albumin R (10%)(RU 486)Aminoglutethimide Oral Rapid 10-15 hr 20%-35% R (35%-50%)Danazol Oral Rapid 15 hr - MAnastrozole Oral Rapid 50 hr 40% M,R

CBG, Corticosteroid-binding globulin; M, metabolism; R, renal; SHBG, sex hormone-binding globulin. * Enterohepatic cycling

Adverse EffectsAdverse Effects1.Major adverse effects : -breast fullness, depression, dizziness, edema, headache, nausea, vomiting2.Cardiovascular : -serious side effects : women > 35 years, smoke -thromboembolism, thrombophlebitis, hypertension, myocardial infarction, cerebral and coronary thrombosis3.Hepatobiliary system -incidence of gallbladder & gallstones

ANDROGENSANDROGENS

Anabolic and/or masculinizing effectsImportant androgen in humans : testosterone

Testosterone :-Embryonic development of the male phenotype ;

sexual development-Secretion by Leydig’s cells

PharmacokineticsPharmacokinetics*Testosterone

-Adm : IM (orally : first-pass metabolism >) -Extensively bound (98%), mostly to SSBG

and also to albumin -E : urine and feces*Testosterone der. (fluoxymesterone & danazol) : t

½ >

ADVERSE EFFECTS AND ADVERSE EFFECTS AND CONTRAINDICATIONSCONTRAINDICATIONS

Masculinization in womenPriapism, impotenceLDL / HDL ratio EdemaCI : pregnant women, cardiovascular

disease, carcinoma of the prostate or hepatic

THERAPEUTIC USESTHERAPEUTIC USES

Prepubertal and post pubertal hypogonadismAnemiaEstrogen-dependent breast cancers 

ANTIANDROGENSANTIANDROGENS

• Competitive inhibitors of androgens • Indications :

- Cyproterone acetate : Th/ Hirsutism in women- Flutamide :

Th/ Prostatic carcinoma